Ординатура / Офтальмология / Английские материалы / Diabetes and Ocular Disease Past, Present, and Future Therapies 2nd edition_Scott, Flynn, Smiddy_2009

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were 2.8 times as likely to develop retinopathy as those in the lowest third (systolic blood pressure < 125 mmHg) [51]. There was no relation of systolic blood pressure with retinopathy progression [51] and no threshold systolic blood pressure was evident [108]. Based on the UKPDS data, each 10 mmHg reduction in systolic blood pressure could be expected to reduce the risk of retinopathy by 10% [51].

Two other clinical trials have provided further evidence that blood pressure control is useful in preventing retinopathy and other microvascular complications in type 2 diabetes. The Appropriate Blood Pressure Control in Diabetes (ABCD) trial, a randomized controlled clinical trial of intensive versus conventional blood pressure control, showed benefit of intensive control in normotensive but not hypertensive patients with type 2 diabetes [109]. The Steno-2 Study showed that in patients with type 2 diabetes and microalbuminuria, an intensive, multifactorial approach that targeted hyperglycemia, hypertension, and dyslipidemia, reduced the risk of retinopathy by 58% as compared to conventional treatment alone [110].

In conclusion, data from epidemiological studies and clinical trials support clinical guidelines to control elevated blood pressure in patients with type 2 diabetes to reduce visual loss from retinopathy, as well as morbidity and mortality from cardiovascular diseases.

Hyperlipidemia. There is increasing evidence that dyslipidemia is an important risk factor for retinopathy and macular edema. Epidemiological studies show an association of dyslipidemia with retinopathy [20,111–117], CSME [20], and possibly proliferative retinopathy [118]. In the WESDR, higher total serum cholesterol was associated with retinal hard exudates in both the youngerand the older-onset groups taking insulin but not in those with type 2 diabetes using oral hypoglycemic agents [119]. In the 2709 patients in the ETDRS in whom serum lipids were measured, higher levels of triglycerides, low-density lipoproteins, and very- low-density lipoproteins at baseline were associated with an increased risk of hard exudates and decreased visual acuity [120].

A recent large clinical trial has provided the initial evidence that lipid-lowering therapy may prevent visual loss from diabetic retinopathy. In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, the effect of fenofibrate on vascular events was examined in 9795 participants with type 2 diabetes who were not taking statin therapy at study entry [121]. Patients had a total cholesterol concentration of 3.0 to 6.5 mmol/L and a total cholesterol/HDLcholesterol ratio of 4.0 or more, or plasma triglyceride of 1.0 to 5.0 mmol/L. After 5 years, participants treated on fenofibrate were less likely to have retinopathy needing laser treatment (5.2% vs 3.6%, p = 0.0003). However, the severity of retinopathy, the indication of laser treatment, and the type of laser treatment (focal or pan-retinal) was not reported in the FIELD study. This study is supported by smaller clinical case series [122–124] that suggest lipid-lowering therapy with statins could be useful as an adjunct therapy to laser treatment. Thus, lipid lowering therapy may be beneficial for patients with diabetes and dyslipidemia not only for its effects on cardiovascular morbidity, but also for its possible effects on retinopathy.

Endogenous and Exogenous Insulin. Whether endogenous and exogenous insulin has an independent effect on risk of diabetic retinopathy is uncertain [125–128]. In the WESDR, persons with undetectable or low plasma C-peptide (a marker for low endogenous insulin) were more likely to have retinopathy and to have more severe retinopathy at baseline [126]. However, there was no relationship between baseline C-peptide level and the incidence or progression of retinopathy in persons with type 1 diabetes [127]. This contrasts somewhat to findings from the DCCT in which lower C-peptide levels were associated with an increased risk of retinopathy [128].

Exogenous insulin has been suggested as a possible cause of both macrovascular and microvascular disease, including retinopathy, in people with type 2 diabetes. However, in the WESDR, there was no association between the amount or type of exogenous insulin used and the presence, severity, incidence or progression of retinopathy in the older-onset group using insulin with high C-peptide levels (0.3 nM or greater) [126,127]. Thus, exogenous insulin is unlikely to be a significant independent risk factor for retinopathy incidence or progression in persons with diabetes.

Proteinuria and Nephropathy. Diabetic retinopathy is closely linked with nephropathy, as both frequently coexist in diabetic patients, and are thought to be microangiopathies reflecting common predisposing factors and pathogenic mechanisms [129]. Longer duration of diabetes, hyperglycemia and hypertension, for example, are well-established risk factors for both retinopathy and nephropathy.

Independent of duration of diabetes, blood pressure, and glycemic control, retinopathy is associated with preclinical morphological changes of diabetic nephropathy in normotensive diabetic patients prior to the development of nephropathy [130]. The presence of retinopathy is also a risk factor for the subsequent development of clinical nephropathy, estimated in one study to be 50% at 5 years, and 75% at 12 years [131]. At the same time, the presence of diabetic nephropathy is a risk factor for the development and progression of retinopathy [132,133]. In the WESDR, younger-onset diabetic persons with gross proteinuria at baseline were 2.3 times more likely to develop proliferative retinopathy over 4 years than those without gross proteinuria [133]. The presence of gross proteinuria at baseline was also associated with a 95% increased risk of developing macular edema among this group in the WESDR 14-year follow-up examination [83]. However, these associations reached only borderline significance when other retinopathy risk factors were controlled for, supporting the fact that similar processes may explain both microvascular complications. For older-onset diabetic patients taking insulin, the relationship was less consistent.

There are clinical case series of patients with renal failure having more severe macular edema that resolves after either peritoneal or hemodialysis [134,135], but no benefit was observed in a small uncontrolled prospective study of diabetic patients with renal failure [136]. There are no clinical trial data to show that interventions that prevent or slow diabetic nephropathy will reduce the incidence and progression of retinopathy.

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Cigarette Smoking and Alcohol Consumption. Cigarette smoking is a known risk factor for atherosclerotic diseases while moderate alcohol consumption has been suggested to be cardioprotective [137,138]. However, most epidemiological studies, including the WESDR, have not found a consistent pattern of association between either smoking [12,15,77,139] or alcohol consumption [26,140] and risk of retinopathy.

Unexpectedly, in the UKPDS, cigarette smoking was suggested to be associated with a reduced incidence of retinopathy [59], while alcohol consumption was found to increase the risk of retinopathy in newly diagnosed men with type 2 diabetes [28]. In the WESDR, alcohol consumption was associated with a lower frequency of proliferative retinopathy in the younger-onset group [139]. However, there was no relationship between alcohol consumption at the 4-year examination and the incidence and progression of retinopathy in either the youngeror olderonset groups at the 10-year follow-up [140].

Obesity. The association between obesity and diabetic retinopathy has been investigated in several studies. Some [12,64,70,81,141–144] but not others [9,77,78,145,146], have documented a relationship between larger body mass index (BMI) and risk of retinopathy. In the WESDR, higher body mass was related to presence and severity of retinopathy only in the older-onset people not using insulin [144]. Those who were underweight at baseline (BMI < 20 kg/m2 for both men and women) were three times more likely to develop retinopathy as those who were of normal weight (BMI of 20–27.7 kg/m2 for men and 20–27.2 kg/m2 for women). It has been suggested that this may reflect a “severe” phase of diabetes in underweight older-onset subjects, or that these underweight patients may be a subset of late-onset type 1 diabetes. Persons obese at baseline (BMI > 31.0 kg/m2 for men and 32.1 kg/m2 for women) were 34% (95% confidence intervals, 0.97, 1.86) more likely to have progression of retinopathy and 41% (95% confidence intervals, 0.76, 2.62) more likely to develop proliferative retinopathy than those who were of normal weight at baseline, although these associations were not statistically significant.

Exercise. Exercise and physical activity may have a positive effect in reducing the risk of diabetic complications, either directly (e.g., lowering blood glucose levels and increasing insulin sensitivity), or indirectly via improved cardiovascular function (e.g., increasing high density lipoprotein (HDL), lowering risk of hypertension). However, there is also the concern that physical activity may have potentially adverse effects on retinopathy in patients with more advanced disease (e.g., risk of vitreous hemorrhage in patients with proliferative retinopathy due to transiently elevated blood pressure).

However, the few epidemiologic data available have not shown a consistent relationship between physical exercise and diabetic retinopathy [147,148]. In the WESDR, women diagnosed with diabetes before 14 years of age who participated in team sports were less likely to have proliferative diabetic retinopathy than those who did not [147]. However, there was no association between physical activity or leisure-time energy expenditure and the presence and severity of

diabetic retinopathy in men. In addition, in a more recent analysis of prospective WESDR data, there was no effect of exercise in preventing retinopathy in either men or women [148].

Pregnancy and Reproductive Measures. Diabetic retinopathy can progress rapidly during pregnancy [149,150], but this is thought to be usually a transient effect. Whether pregnancy is an independent risk factor for long-term incidence and progression of retinopathy is less clear. In the WESDR, when compared with nonpregnant diabetic women of similar age and duration of diabetes, pregnant women were more likely to develop retinopathy and have progression of retinopathy, when the groups were followed for a time interval about equal to the length of the pregnancy and when other risk factors were accounted for [150]. Similar findings have been reported in other studies [151,152]. In addition, progression of retinopathy was increased in pre-eclamptic diabetic women when compared to those without preeclampsia [153]. While the mechanisms underlying this exacerbation are unclear, retinal hemodynamics are altered by pregnancy [154,155] and progesterone may induce the production of vascular endothelial growth factor [156].

In pregnancy, the risk factors for retinopathy progression are similar to retinopathy risk factors in nonpregnant diabetic individuals, and include poorer glycemic control, longer duration of diabetes prior to pregnancy, and presence of concomitant hypertension [151,153,157]. The Diabetes in Early Pregnancy Study, a prospective study of 140 pregnant diabetic patients, showed that women with the poorest glycemic control at baseline, but with the greatest reduction in HbA1c during the first trimester, were at increased risk of retinopathy progression [151]. These findings underscore the importance of good metabolic and blood pressure control and close monitoring of retinopathy status in diabetic patients who are pregnant.

The higher risk of developing retinopathy after puberty may be related to sex hormones. In the WESDR, menarchal status at the baseline examination was related to the prevalence and severity of retinopathy [158]. However, increased estrogen occurring with puberty is unlikely to be an important risk factor, because use of oral contraceptives does not appear to increase the risk of retinopathy [159]. Similarly, use of hormone replacement therapy has not been found to increase the risk of diabetic retinopathy in the WESDR [160].

Infl ammation. Chronic inflammation and dysfunction of the vascular endothelium have been proposed as possible pathogenic factors in type 2 diabetes development [161,162]. There is increasing evidence from animal models and human studies that chronic inflammation and glucose-induced arteriolar endothelial dysfunction are related to development, severity, and progression of diabetic retinopathy [163–165]. Studies have shown that inflammatory protein levels of cytokines, chemokines, and adhesion molecules are elevated in both the vitreous [166] and serum [167] of patients with diabetic retinopathy. Epidemiological studies have provided further support. In the Hoorn study and the EURODIAB Prospective Complications Study, systemic markers of inflammation and endothelial activitation (e.g., C-reactive protein, soluble intercellular adhesion molecule-1, von Willebrand factor) were

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associated with retinopathy, independent of other risk factors [168,169]. However, whether anti-inflammatory treatment can delay the onset or progression of retinopathy is unclear. In the ETDRS, patients with mild-to-severe nonproliferative diabetic retinopathy (NPDR) or early proliferative diabetic retinopathy (PDR) were assigned randomly to either aspirin (650 mg per day) or placebo. Aspirin did not prevent the development of high-risk PDR and did not reduce the risk of visual loss, or increase the risk of vitreous hemorrhage [170].

MORBIDITY AND MORTALITY ASSOCIATED WITH RETINOPATHY

Diabetic retinopathy, reflecting systemic microvascular dysfunction, may be linked with cardiovascular diseases elsewhere in the body [55]. In the WESDR, participants with proliferative retinopathy had a higher risk of incident myocardial infarction, stroke, nephropathy, and lower leg amputation as compared to those with no or minimal retinopathy at baseline [171]. In younger-onset diabetics, after adjusting for age and sex, retinopathy severity was associated with all-cause and coronary heart disease mortality, and in older-onset persons with all-cause, coronary heart disease mortality, and stroke [172]. After controlling for systemic factors, only the associations with all-cause and stroke mortality in older-onset persons remained. In the ARIC study, the presence of retinopathy was associated with a four-fold risk of congestive heart failure among type 2 diabetic participants without previous coronary heart disease or hypertension, independent of standard risk factors [173].

Epidemiological studies in fact indicate that typical retinopathy signs predict systemic vascular diseases even in persons without diabetes [173]. In the ARIC study, retinopathy was associated with twoto four-fold risk of incident clinical stroke, independent of blood pressure, cigarette smoking, lipids, and other risk factors [66]. Among participants without stroke or transient ischemic attack, retinopathy was significantly related to magnetic resonance imaging (MRI)-defined cerebral white matter lesions, which are markers of subclinical small vessel cerebral disease [67].

These data suggest that the presence of retinopathy in both diabetic and nondiabetic patients may be an indicator for increased cardiovascular risk, and may, therefore, help identify individuals who should be under close scrutiny for systemic vascular diseases.

CONCLUSION

Prevention of diabetes, diabetic retinopathy, and other microvascular and macrovascular complications is an important goal in reducing the public health impact of diabetes. Clinical trials have demonstrated that, until approaches for primary prevention of diabetes itself become available, secondary prevention through risk factor reduction (e.g., controlling hyperglycemia and hypertension) can reduce the incidence and progression of retinopathy and visual loss. Because retinopathy may progress despite good glycemic and blood pressure control, it is important that early detection of retinopathy through comprehensive dilated eye examinations by appropriate eye care providers be performed.

SUMMARY FOR CLINICIANS

•Retinopathy is the most common specific complication of patients with diabetes.

•The risk of retinopathy is strongly associated with duration of diabetes. Between 60% and 90% of persons who have diabetes for 15 years or longer will have signs of retinopathy.

•Hyperglycemia is an important modifiable risk factor for the development and progression of retinopathy in both type 1 and type 2 diabetes. In the DCCT, a 1% reduction in HbA1c levels is associated with an approximately 30% reduction in risk of retinopathy in type 1 patients. In the UKPDS, a similar 1% reduction in HbA1c levels is associated with an approximately 20% reduction in the risk of retinopathy in type 2 patients.

•Hypertension is another important risk factor for retinopathy in type 2 patients. The UKPDS showed that a 10 mmHg reduction in systolic blood pressure is associated with a 10% reduction in the risk of retinopathy. Moreover, the beneficial effects of tight blood pressure control appear to additive and independent of tight glycemic control.

•Lipid-lowering therapy may be useful as an adjunct in the management of diabetic retinopathy. However, there have been no large randomized clinical trials that have shown efficacy of lipid-lowering therapy in reducing the risk of macular edema or progression of retinopathy.

•The presence of retinopathy in both diabetic and nondiabetic patients may be an indicator for increased cardiovascular risk.

•Comprehensive dilated eye examinations are important for early detection of sight-threatening retinopathy in patients with diabetes.

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